Direct protein-protein coupling enables cross-talk between dopamine D5 andgamma-aminobutyric acid A receptors

GABAA (gamma-aminobutyric-acid A) and dopamine D1 and D5 receptors represen t two structurally and functionally divergent families of neurotransmitter receptors, The former comprises a class of multi-subunit ligand-gated chann els mediating fast interneuronal synaptic transmission, whereas the latter belongs to the seven-transmembrane-domain single-polypeptide receptor super family that exerts its biological effects, including the modulation of GABA (A) receptor function, through the activation of second-messenger signallin g cascades by G proteins, Here we show that GABA(A)-ligand-gated channels c omplex selectively with D5 receptors through the direct binding of the D5 c arboxy-terminal domain with the second intracellular loop of the GABA(A) ga mma 2(short) receptor subunit, This physical association enables mutually i nhibitory functional interactions between these receptor systems, The data highlight a previously unknown signal transduction mechanism whereby subtyp e-selective G-protein-coupled receptors dynamically regulate synaptic stren gth independently of classically defined second-messenger systems, and prov ide a heuristic framework in which to view these receptor systems in the ma intenance of psychomotor disease states.